Substance-P, widely distributed throughout the periphery and central nervous system, is believed to mediate a variety of biological actions, via an interaction with three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation.
Accordingly, compounds capable of antagonizing the effects of substance-P at NK.sub.1 receptors will be useful in treating or preventing a variety of brain disorders including pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including Parkinson's disease, multiple sclerosis, and Alzheimer's disease; and ophthalmic diseases including scleroderma.
The compounds of the invention provide NK.sub.1 receptor antagonists useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth. They will also be useful as agents for imaging NK.sub.1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
The compound, 2-benzofuranylmethyl [R-(R*,S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amin o]ethyl]carbamate (hereinafter compound 1) is a highly selective NK.sub.1 antagonist useful as a pharmacologic agent in the treatment of, for example, emesis. The chemical structure of compound 1 is ##STR2##
Compound 1, processes for its preparation, and methods of using it are claimed in U.S. Pat. No. 5,594,022 hereby incorporated by reference. U.S. patent application Ser. No. 60/021030 claims the use of compound 1 as an antiemetic; it is hereby incorporated by reference.
Compound 1 is poorly soluble in water (less than 1 .mu.g/mL). Therefore, a suitable pharmaceutical formulation, especially an intravenous formulation, is not conveniently achievable using the parent drug substance. The instant invention is a solution to this problem; it is a prodrug of compound 1 with increased aqueous solubility, good solution stability, and high conversion rate to the parent compound in vivo by an enzyme such as an alkaline phosphotase or an esterase. The instant invention utilizes an attachment to the parent molecule, directly or indirectly, of biocleavable, ionizable group(s) such as a phosphate or an amino acid derivative for enhancing aqueous solubility. Due to the lack of readily derivatized functional groups, the only available sites of attachment on compound 1 are the nitrogen of the amide bond; the carbamate bond, and the indole moiety. Although prodrugs derived from amide and carbamate functionalities have been studied in the past, the nitrogen of the indole ring was selected as a more favorable site for prodrug derivatization due to its pKa, chemical reactivity, and relatively less steric encumbrance.
The use of indole nitrogen as the functional group for the preparation of prodrugs is not known in literature. It is the intention of this application to provide a novel prodrug approach by utilizing the indole nitrogen for the preparation of prodrugs. We have now discovered that a hydrophilic and ionizable group, such as a phosphate or an amino acid derivative attached directly or indirectly to an indole nitrogen, can be cleaved enzymatically in vivo. In the indirect attachment approach, a variety of self-cleavable linkers, which were reported to be useful for the hydroxy and amino functional groups in the preparation of prodrugs, were found to be also successful for the indole nitrogen. These linkers include hydroxymethyl (Varia S. A., Schuller S., Sloan K. B., Stella V. J., "Phenytoin prodrugs III: water-soluble prodrugs for oral and/or parenteral use," J. Pharm. Sci.,1984;73: 1068-1073; TenHoor C. N., Stewart B. H., "Reconversion of fosphenytoin in the presence of intestinal alkaline phosphatase," Pharm. Res.,1995;12:1806-1809), hydroxymethoxycarbonyI (Safadi M., Oliyai R., Stella V. J., "Phosphoryloxymethyl carbamates and carbonates-novel water-soluble prodrugs for amines and hindered alcohol," Pharmaceutical Res., 1993;10:1350-1355), and masked lactones (Amsberry K. L., Borchardt R. T., "The lactonization of 2'-hydroxyhydrocinnamic acid amides: a potential prodrug for amines," J. Org. Chem., 1990;55:5867-5877; Amsberry K. L., Gerstenberger A. E., Borchardt R. T., "Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug," Pharmaceutical Res., 1991;8:455-461; Nicolaou M. G., Yuan C-S., Borchardt R. T., "Phosphate prodrugs for amines utilizing a fast intramolecular hydroxy amide lactonization," J Org. Chem.,1996;61 :8636-8641). We have now also discovered that prodrugs of compound 1 derived from both phosphate and amino acid derivatives provide reasonable aqueous solubility and good bio-conversion to the parent compound in vivo.